Field of the inventionThe present invention relates to a device fordetecting an analyte in a sample belonging to a class ofdevices known as chemically-sensitive field-effecttransistors (CHEMFET's) which are of particular interestfor biomedical and industrial applications.
Background of the inventionThere is considerable interest in methods fordetection, measuring and monitoring chemical properties ofa sample. A sample can be a solid, solution, gas, vapouror a mixture of those. The chemical properties of thesample are determined by the analyte present in the sample,the analyte can be e.g. an electrolyte, a biomolecule or aneutral molecule.
Chemical sensors belonging to a class ofdevices known as Chemically Sensitive Field-EffectTransistors (CHEMFET's) are of particular interest forbiomedical and industrial applications. Chemicallysensitive field-effect transistors measure chemicalproperties of the samples to which the device is exposed.In a CHEMFET, the changes at the surface of the gate dielectric are detected via the modulations of the electricfield in the channel of a field-effect transistor. Suchchemical changes can be induced by e.g. the presence ofions in aqueous solutions, but also by the interaction ofan electroinactive organic compound with a biological-sensingelement in contact with the gate of the field-effecttransistor. In this way, the concentration of ionsor organic biomolecules (e.g. glucose, cholesterol, etc) inaqueous solutions can be measured. One promisingapplication of this type of device regards the monitoringof the cell metabolism for fundamental research or drug-characterizationstudies.
Among CHEMFET devices, the ion-sensitivefield-effect transistors are best known. The concept ofion-sensitive field-effect transistor (ISFET) has beenintroduced by P. Bergveld in 1970 [P. Bergveld,IEEE Trans.Biomed. Eng., BME-17, 1970, pp. 70]. It was demonstratedthat when the metal gate of an ordinary MOSFET is omittedand the dielectric layer is exposed to an electrolyte, thecharacteristics of the transistor are affected by the ionicactivity of the electrolyte. The schematic drawing of aclassic ISFET is shown in figure 1. The siliconsubstrate(1) of the device acts as current pathway betweenthe source region (3) and the drain region (2). Bothregions are contacted by metal electrodes (5). Thedielectric layer (4) is covered with an ion-selectivemembrane (6) which is exposed to the solution (7). Thedevice is encapsulated with an encapsulating material (9).Optionally, a reference electrode (8) can be present.ISFET's have first been developed for pH and Na+ activitydetection in aqueous solutions (C. D. Fung, P.W. Cheung andW. H. Ko,IEEE Trans. El. Dev., Vol. ED-33, No.1, 1986,pp.8-18). The cation-sensitivity of the device isdetermined by the ionization and complexation of the surface hydroxyl groups on the gate dielectric surface.ISFET devices for Ca2+, K+ activity monitoring have alsobeen fabricated. The sensitivity towards these ions isachieved by incorporating a sensitized plastic membrane(PVC) in contact with the gate dielectric. Therefore, thesesensors detect changes in the charge of the membrane or inthe transmembranar potential. Besides the use of CHEMFETdevices for the determination of ions (ISFET), CHEMFET'shave also been employed as enzyme-sensitive FET (ENFET's)for organic molecule detection or immuno-sensitive FET's(IMFET's) for immunochemicals (antigen, antibody)monitoring.
CHEMFET's exhibit important advantages overconventional chemically selective electrodes. Usually,CHEMFET's are fabricated with standard CMOS technology,which offers the advantages of miniaturization and massproduction. In the biomedical field, there is anespecially important area for the application ofminiaturized sensors. The sensor is mounted in the tip ofindwelling catheters, through which their feasibility formonitoring blood electrolytes and parameters has beendemonstrated.
The fabrication method offers the additionalbenefit of the fabrication of multi-ion sensors andintegration in smart sensors and sensor arrays. A furtheradvantage of the use of CHEMFET is the logarithmic responseof the potential in function of the analyte concentration,this type of response is interesting if a broadconcentration range is investigated. Since the response ofa CHEMFET device is initiated by the field-effect, thisresponse is very fast compared to the response ofconventional chemically sensitive electrodes. Up to now,all CHEMFET devices are based on silicon or silicon basedmaterials.
However, there are some problems that so farhave hampered the commercial applications of these devices.The most important problem of the CHEMFET is the drift ofthe device. Drift is typically characterized by arelatively slow, monotonic temporal change in the thresholdvoltage of the FET. As a result, an incorrect estimationof the chemical properties (e.g. ion activity) of thesample will be determined. This problem is more pronouncedfor determination of e.g. physiological ion activities orconcentrations, where a high accuracy is required (e.g.blood electrolytes monitoring). Therefore, the use ofsilicon-based CHEMFET's in this kind of applications isvery reduced. A further limiting factor for the use ofCHEMFET devices is the higher manufacturing cost of thesedevices. For medical application, one is mostly interestedin throw-away devices, which implies very cheap devices.For medical and pharmaceutical applications, devices whichcan be integrated in plastic materials, are most suitable.For silicon-based CHEMFET, the integration in plasticmaterial is not straightforward.
In the prior art, thin film transistors basedon organic materials have been fabricated. Garnier(Garnier F., Hajlaoui R., Yassar A., Srivastava P.,Science, 1994, Vol. 265, p 1684) proposes the use polymericmaterials in a thin film transistor. The choice ofpolymeric materials is determined by the application of thedevice, i.e. as transistor.
Organic materials, and more especiallypolymeric materials, have already been used as sensitiveparts in combination with a solid-state transducer(inorganic material) or as membranes for immobilization ofbiomolecules (e.g. enzymes) for specific interactions (G.Harsányi,Polymer Films in Sensor Applications -Technology, Materials, Devices and Their Characteristics, TECHNOMIC Publishing Co. Inc. Lancaster-Basel, 1995, p 53-92and p 149-155; G. Bidan,Sensors and Actuators B,Vol 6,1992, pp. 45-56). In the electroconducting conjugatedpolymers-based (ECP-based) chemical sensors, there is adirect interaction between the EPC layer and the analyte todetect. The detection mechanism is based on the ionexchange between the ECP layer and the sample. Therefore, adoped ECP layer is needed. A major disadvantage is therequired electrochemical deposition of the conductinglayer, because this deposition technique is ratherdifficult to control, which results in the deposition oflayers with a lower uniformity and reproducibility.Moreover, the electrochemical deposition of dopedconjugated polymeric layers also implies a morecomplicated, multi-step process. Besides this, due to theelectropolymerization reactions, the electroconductingconjugated polymer layer is always p-doped, which meansthat only anions can be detected. Furthermore, thedeposition process requires electrodes made of metallicmaterial-or glassy carbon.
Aim of the inventionOne aim of the invention is to describe animproved device for detecting an analyte in a sample whichcombines the advantages of existing CHEMFET devices withadvantageous properties such as low price, disposability,reduced drift of the device and suitability for biomedicaland pharmaceutical applications.
Summary of the inventionIn a first apect af this invention , a devicefor detecting an analyte in a sample is disclosedcomprising an active layer comprising at least a dielectricmaterial, a source electrode, a drain electrode and a semiconducting layer for providing a current pathwaybetween said source electrode and said drain electrode, theconductance of said semiconducting layer being influencedby interaction of said active layer with said samplecontaining said analyte to detect, wherein saidsemiconducting substrate consists of an organic containingsemiconducting material. Analyte, as used herein, shall beunderstood as any chemical molecule, atom or ion comprisingbut not limited to ions, neutral molecules and biomoleculeslike enzymes, immunochemicals, hormones and reduciblegases. Sample, as used herein, shall be understood as asolid, solution, gas, vapour or a mixture of thosecomprising at least the analyte. For the purpose of thisinvention, detecting shall mean determining,identification, measuring of concentrations or activities,measuring a change of concentrations or acrivities of atleast one analyte present in the sample.
In an embodiment of the invention, the activelayer comprises a dielectric layer.
In an embodiment of this invention, thedielectric layer consists of a material with a dielectricconstant higher than 3. In order to maximize the currentflow between source and drain, the value of the dielectricconstant must be as high as possible. Furtheron, adielectric material with a high value of the dielectricconstant will reduce the operational voltage of the device.The chemically selective dielectric layer can be chosensuch that the material of the dielectric layer isessentially inert to the sample. Inert shall, at least forthe purpose of this application, means that the capacitanceof the dielectric layer without functionalization remainpractically constant. Thus, the problems related to thedrift of the device can be eliminated. The drift phenomenais typically observed for silicon-based devices, since the silicon layer can be modified when exposed to the sample,resulting in a change of the capacitance of the dielectriclayer. This results in slow, temporal change in thethreshold voltage, which implies an incorrect estimation ofthe detection of the analyte.
In an embodiment of the invention, the activelayer consists essentially of a dielectric layer. Thedielectric layer is made of an active material adapted toselectively react with said analyte when said device isexposed to said sample containing said analyte. Dependingon the application, the dielectric layer which is exposedto the sample can be modified in such a way that there isan interaction between the analyte and the modifieddielectrical material.
In an embodiment of the invention, thedielectric layer comprises an organic dielectric material.In a further embodiment of the invention, the dielectriclayer comprises an inorganic containing material. The valueof the dielectric capacictance is preferably as high aspossible. The value of the dielectric constant, , of thedielectric material is higher than 3, and preferably higherthan 5 and preferably higher than 10 and preferably higherthan 100.
In a further embodiment of the invention, theactive layer can further comprises a dielectric layer and amembrane layer. Said membrane layer is made of activematerial and is adapted to selectively react with saidanalyte when the device is exposed to the sample containingthe analyte. Preferably, the chemically sensitive membraneis a conjugated oligomer or a polymer.
In a further embodiment of the first aspectof the invention, the source and drain electrode comprisean organic containing material characterized in that saidthe surface resistance of the electrodes is lower than 100Ω/sq. The source and drain electrode can have aninterdigitated configuration.
In a further embodiment of this invention,the device can additionaly comprise an encapsulating layerto protect said current pathway between said sourceelectrode and said drain electrode and a a support layerwherein said encapsulating layer and support layer are madeof organic containing material.
In a second aspect of this invention, asystem for detecting an analyte in a sample is disclosed,comprising a device as described in the first aspect ofthis invention, and a reference field-effect transisitor.
Brief description of the drawingsFig.1: Description of an ion-sensitive field-effecttransistor (ISFET) fabricated with CMOS technology(H. H. van den Vlekkert et. al.,Proc. 2nd Int. Meeting onChemical Sensors, Bordeaux, France, 1986,pp. 462.)
Fig.2 a-b: Configuration of device accordingto the present invention
Fig.3: Interdigitated source-drain electrodesconfiguration.
Detailed description of the inventionIn relation to the appended drawings thepresent invention is described in detail in the sequel.Several embodiments are disclosed. It is apparent howeverthat a person skilled in the art can imagine several otherequivalent embodiments or other ways of practicing thepresent invention, the spirit and scope thereof beinglimited only by the terms of the appended claims.
A device for detecting an analyte in asample, based on organic materials is described. The device can be a chemically sensitive field-effectivetransistor (CHEMFET). Said device is a thin filmtransistor in which the gate electrode is missing and whichcomprises an active layer. Said active layer comprises atleast a dielectric layer which is exposed to a samplecomprising an analyte to be investigated directly or via alayer with a specific recognition function. Said devicecan be used for e.g. the detection and measuring ofconcentrations and activities of chemical species (analyte)present in the sample. Analyte, as used herein, shall beunderstood as any chemical molecule, atom or ion comprisingbut not limited to ions, neutral molecules and biomoleculeslike enzymes, immunochemicals, hormones and reduciblegases. Sample, as used herein, shall be understood as asolution, solid, gas, vapour or a mixture of thosecomprising at least the analyte. For the purpose of thisinvention, detecting shall mean determining,identification, measuring of concentrations or activities,measuring a change of concentrations or acrivities of atleast one analyte present in the sample. Particularly, saiddevice can be used for the detection of analytes in samplesin the biochemical and pharmaceutical field. Furthermore,said device can be used for the detection in samplescontaining specific analytes e.g. vapours, odeur, gases.
In this invention, a device for detecting ananalyte in a sample is disclosed, comprising asemiconductor layer, a source electrode, a drain electrodeand an active layer. The active layer comprises at least adielectric material. The semiconducting layer can bechosen such that it acts as current path between source anddrain electrode. The electric field in the channel of thedevice is modified by the interaction of said active layerwith an analyte in a sample. The choice of saidsemiconducting material can be further based on the conductivity of the material, the stability of thematerial, their availability, their compatibility withstandard processing steps as used in the manufacturing ofintegrated circuits, their deposition characteristics andtheir cost price.
Said semiconducting layer can be adjacent tothe active layer or can not be adjacent to the activelayer.
The direct interaction of the semiconductinglayer with the analyte is preferably negligible. In thisinvention, the semiconducting layer comprises an organiccontaining semiconducting material. The organic containingsemiconducting material can be used in its neutral(undoped) state and can be a p-type semiconductore or an n-typesemiconductor but preferably a p-type semiconductor.Said organic containing semiconducting material can be anorganic polymer e.g. a conjugated polymers. Saidconjugated polymer can be but is not limited toPolythiophene (PT), poly(p-phenylene) (PPP), poly(p-phenylenevinylene) (PPV), poly(2,5-thiophene vinylene)(PTV), polypyrrole (PPy) or C60-buckminster fullerene. Theorganic containing semiconducting layer can also be aconducting oligomer layer wherein said oligomer layer canbe but is not limited to - hexylthiophene ( -6T),pentacene and oligo-phenylene vinylene.
The deposition of the organic containingsemiconducting layer can be done by spin-coating, castingor evaporation of solution processible long-chain polymeror oligomer evaporation. Problems mentioned in the prior-artrelated to the deposition of electroconducting polymersare avoided by using the above mentioned depositiontechniques.
In this invention, a device for detecting ananalyte in a sample is disclosed, comprising a semiconductor layer, a source electrode, a drain electrodeand an active layer.
Said active layer is chosen such that it assures the field-effectgeneration and thus the current flowing in thetransistor channel. The active layer comprises at least adielectric material. Preferably, the active layer consistsof a dielectric layer or a dielectric layer covered with ananalyte-specific membrane. In order to maximize thecurrent flowing between source and drain, the dielectriccapacitance is preferably as high as possible. This can beachieved by depositing the dielectric material in very thinlayers and by using materials with a high dielectricconstant. The thickness of the layers is typically from0.1µ up to 0.5 µ. The dielectric constant, , of thedielectric material is higher than 3, and preferably higherthan 5 and preferably higher than 10 and preferably higherthan 100. The water absorption of the active layer ispreferably as low as possible and preferably negligible.The drift of the device, as mentioned in the background ofthe invention can be avoided or at least reduced by using adielectric layer which is inert to the sample. Inertshall, at least for the purpose of this application, meanthat the capacitance of the dielectric layer withoutfunctionalization remain practically constant. Moreover,taking into account that organic containing semiconductingmaterials have a large density of trapping levels in theband gap, a dielectric material with a high ε value willreduce the operational voltage. This is an significantadvantage compared to the prior art for devices with aspecific sensing function such as the CHEMFET devices.
The dielectric layer can be chosen such thatit has a specific sensitivity towards the chemical specieswhich must be detected or measured. The dielectric layer can comprise an organic containing dielectric material oran inorganic containing dielectric material.
When the dielectric layer comprises an organic containingmaterial and in order to achieve the specific chemicalsensitivity, the surface of the dielectric layer must befunctionalized. Functionalisation means that the chemicalproperties of the dielectric material in contact with thesample are modified in such a way that there is aninteraction between the analyte and the modifieddielectrical material. The functionalisation depends onthe nature of the analyte to detect. The analyte which hasto be detected can be, but is not limited to an ion, anorganic biomolecule or metabolic biomolecules. When theanalyte is an ion, ion-selective groups are synthesized one.g. a polymer or an oligomer. For the detection of ionslike Na+, K+, Ca2+, Mg2+, Cl- or any other ion, the ion-selectivegroups can be selected from the group comprisinge.g. a crown-ether, a cryptand, or any other ion-complexforming chemical group. Organic biomolecules can bedetected via e.g. an enzymatic reaction, that leads to achange in e.g. the pH. This pH change will be used for thedetection and measuring of the enzymatic reaction. The sameprinciple is used for monitoring the cellular metabolismwhen the enzymatic layer is replaced by a layer of cells.Also, the recognition molecule can be entrapped in a matrixof the dielectric material.
The dielectric material can also comprise aninorganic containing material. Said inorganic containingmaterial can comprise an inorganic oxide, an inorganicnitride or an inorganic oxynitride. Said inorganiccontaining material can comprise an amorphous metallicmaterial selected from the group comprising TiO2, BaTiO3,BaxSr1-xTiO3, Pb(ZrxT1-x)O3, Ta2O5, SrTiO3, BaZrO3, PbTiO3,LiTaO3 etc . When the inorganic containing material has a specific recognition function towards the analyte, thedielectric layer is exposed directly to the analyte. Fore.g. an inorganic oxide, protons or concentrations ofprotons can be detected or measured by direct exposure ofthe dielectric layer to the sample containing the analyte
The organic or inorganic containingdielectric layer can also show no specific recognitionfunction towards the analyte. Therefor, an analyte-specificmembrane is deposited on the dielectric layer. Themembrane layer is made of an active material. The analytespecific membrane can be a polymeric matrix which containsthe specific recognition molecule. Possible polymericmaterials and specific recognition molecules are given inG. Harsányi,Polymer Films in Sensor Applications -Technology, Materials, Devices and Their Characteristics,TECHNOMIC Publishing Co. Inc. Lancaster-Basel, 1995, pp.2.and W. Gopel, J. Hesse, J. N. Zemel,Sensors: AComprehensive Survey, Vol.2, Part.I, 1991, pp.467-528. Theanalyte specific membrane can be but is not limited to aPVC matrix, polysiloxane-based membranes and Langmuir-Blodgettfilms. Said specific recognition molecule can be,but is not limited to valinomycin for K+ detection,specific enzymes for detecting organic inactive species(glucose, cholesterol).
In this invention, a device for detecting ananalyte in a sample is disclosed, comprising a sourceelectrode, a drain electrode, a semiconductor layer and anactive layer.
The source electrode and the drain electrodecan be made of an organic containing material. The organiccontaining material can be chosen such that theconductivity of the material is in the metallic range. Thesurface resisitance of the the electrodes is preferablylower than 100Ω/sq. Electrodes made of organic containing material are preferred because this results in an optimalquality of the contact between the electrodes and theorganic containing semiconducting layer. Said organiccontaining material can be a polymer or an oligomer. Thepolymer can be but is not limited to polyaniline doped withcamphor sulphonic acid. The source and drain electrode canalso be made of a metal like gold, platinum or aluminum,depending on the HOMO and LUMO energy levels in the organicsemiconductor. The source and drain electrodes arepreferably patterned lithographycally. The source anddrain electrodes can have an interdigitated configuration,as it is illustrated in figure 3, in order to achievemaximum electric current flowing into the transistorchannel. The channel width (1)-to-length(2) ratio, and thenumber of fingers must be optimized in order to achieve thedesired level for the output current. This configuration ispreferred because of the low conductance of the organiccontaining semiconductor material.
In a further embodiment of the presentinvention, said device further comprises a support layer.The support layer is chosen such that it assures thedeposition of the active layers and that it maintains theflatness of the device. The support can be made ofpolymeric material with a high chemical resistance andthermal properties which are determined by the furtherdeposition steps. The upper working temperature of saidsupport layer is higher then 100 degrees celcius, higherthan 150 degreespolyvinyldifluoride, high densitypolyethylene, polyimide, polytetrafluoroethylen (teflon™),polypropylene or any other material which fulfills theabove mentioned properties.
Furthermore, the device can be encapsulatedby an encapsulating layer. The semiconducting layer andthe electrodes are encapsulated such that the current pathway between source and drain electrode in thesemiconducting layer is protected from the air and from thesample. The encapsulating layer can be made, but is notlimited to an epoxy resin or parylene
Preferred embodiment of the inventionFig. 2B represents a device for detecting ananalyte in a sample according to the present invention.Said device can be a chemical selective field-effecttransistor. Besides the structure of the CHEMFET, a methodis disclosed which can be used for the manufacturing of asingle sensor or an array of sensors. Such sensor arrayhas a multitude of sensing sites, each sensing site being asensor. In a preferred embodiment, the inert support layeris a common support layer of the array.
A support substrate (1) selected according tothe further processing steps as known in the integratedcircuit manufacturing. In a next step, a dielectric layer(2) deposited on the support layer. The dielectricmaterial is an inorganic oxide and can be selected from theinorganic oxides mentioned above. The dielectric layer isdeposited by RF sputtering at a temperature range from 5degrees Celcius to 50 degrees Celcius and preferably atroom temperature. The thickness of the dielectric layer ispreferably about 0.1 µ. In a next step, the source anddrain electrode are deposited. First, a layer of anorganic containing material, e.g. doped polyanaline withcamphorsulfonic acid, is deposited on the dielectric layer.Subsequently, the layer will be patterned lithographycallysuch that the source electrode (3) and the drain electrode(4) are formed. Then, the organic containingsemiconducting layer (5) is deposited on both electrodesand on the remaining dielectric layer. The semiconducting layer has preferably a thickness between between 0.1 and0.5µm and is deposited by spin-coating. An encapsulatinglayer is formed such that the source and drain electrodesand the semiconducting layer are protected from air andfrom the sample. In a last step, an analyte specificmembrane (6) is deposited on the dielectric layer andadjacent to holes formed in the support layer. Thecomposition of the membrane depends on the nature of theanalyte to detect.
Since organic containing materials is areinvolved in the most processing steps, the temperaturerange for all processing steps is as low as possible andpreferably lower than 300 C.
In a further embodiment of this invention, astructure as represented in figure 2A is disclosed.
The device as described can be used with orwithout a reference electrode. A reference electrode or areference FET can be used, depending on the measurementmethod. For instance, in the fixed gate voltage mode, thechemical environment (e.g. aqueous solution) is kept at afixed potential in respect to the sensor source electrode,and the electric current flowing between source and drainelectrodes is recorded in function of the changes in thechemical environment of the sensor. This is realized byadjusting the voltage drop between the source electrode(which is usually grounded) and a reference electrode orreference FET. Also, in the constant drain current mode,the current between source and drain is kept constant byadjusting the voltage drop VGS between the referenceelectrode or reference FET and the source electrode. Theresponse of the sensor is the variation of this voltagedrop, VGS, in function of the changes in the chemicalenvironment.